A genome-wide association meta-analysis of preschool internalizing problems

Kelly S Benke; Michel G Nivard; Fleur P Velders; Raymond K Walters; Irene Pappa; Paul A Scheet; Xiangjun Xiao; Erik A Ehli; Lyle J Palmer; Andrew J O Whitehouse; Frank C Verhulst; Vincent W Jaddoe; Fernando Rivadeneira; Maria M Groen-Blokhuis; Catharina E M van Beijsterveldt; Gareth E Davies; James J Hudziak; Gitta H Lubke; Dorret I Boomsma; Craig E Pennell; Henning Tiemeier; Christel M Middeldorp; Early Genetics and Lifecourse Epidemiology Consortium

doi:10.1016/j.jaac.2013.12.028

A genome-wide association meta-analysis of preschool internalizing problems

J Am Acad Child Adolesc Psychiatry. 2014 Jun;53(6):667-676.e7. doi: 10.1016/j.jaac.2013.12.028. Epub 2014 Feb 19.

Authors

Kelly S Benke¹, Michel G Nivard², Fleur P Velders³, Raymond K Walters⁴, Irene Pappa⁵, Paul A Scheet⁶, Xiangjun Xiao⁷, Erik A Ehli⁸, Lyle J Palmer⁹, Andrew J O Whitehouse¹⁰, Frank C Verhulst¹¹, Vincent W Jaddoe¹², Fernando Rivadeneira¹¹, Maria M Groen-Blokhuis¹³, Catharina E M van Beijsterveldt¹⁴, Gareth E Davies¹⁵, James J Hudziak¹⁶, Gitta H Lubke¹⁷, Dorret I Boomsma¹⁸, Craig E Pennell¹⁹, Henning Tiemeier¹¹, Christel M Middeldorp²⁰; Early Genetics and Lifecourse Epidemiology Consortium

Affiliations

¹ Johns Hopkins Bloomberg School of Public Health, Baltimore, USA and the Samuel Lunenfeld Research Institute, University of Toronto, Toronto, Canada. Electronic address: [email protected].
² VU University Amsterdam, The Netherlands and the Neuroscience Campus Amsterdam, VU University.
³ Erasmus Medical Center, Rotterdam, The Netherlands and The Generation R Study Group, Erasmus Medical Center.
⁴ University of Notre Dame, Notre Dame, USA.
⁵ School of Pedagogical and Educational Sciences, Erasmus University Rotterdam, the Generation R Study Group, and Erasmus University Medical Center-Sophia Children's Hospital.
⁶ University of Texas / M. D. Anderson Cancer Center, USA.
⁷ University of Texas / M. D. Anderson Cancer Center.
⁸ Avera Institute for Human Genetics, Sioux Falls, SD, USA.
⁹ Samuel Lunenfeld Research Institute, University of Toronto, and the Ontario Institute for Cancer Research, Toronto, Canada.
¹⁰ Telethon Institute for Child Health Research, Subiaco, Australia, The Centre for Child Health Research, The University of Western Australia, Perth and the School of Psychology, The University of Western Australia, Crawley.
¹¹ Erasmus Medical Center.
¹² Erasmus Medical Center, and The Generation R Study Group.
¹³ VU University Amsterdam and EMGO+ Institute for Health and Care Research, VU University Medical Center.
¹⁴ VU University Amsterdam.
¹⁵ Avera Institute for Human Genetics.
¹⁶ Vermont Center for Children, Youth, and Families, and the University of Vermont, College of Medicine, Vermont, USA.
¹⁷ University of Notre Dame and with VU University Amsterdam.
¹⁸ Neuroscience Campus Amsterdam, VU University Amsterdam, and EMGO+ Institute for Health and Care Research, VU University Medical Center.
¹⁹ School of Women's and Infants' Health, The University of Western Australia.
²⁰ Neuroscience Campus Amsterdam, VU University Amsterdam, and GGZinGeest/ VU University Medical Center.

PMID: 24839885
DOI: 10.1016/j.jaac.2013.12.028

Abstract

Objective: Preschool internalizing problems (INT) are highly heritable and moderately genetically stable from childhood into adulthood. Gene-finding studies are scarce. In this study, the influence of genome-wide measured single nucleotide polymorphisms (SNPs) was investigated in 3 cohorts (total N = 4,596 children) in which INT was assessed with the same instrument, the Child Behavior Checklist (CBCL).

Method: First, genome-wide association (GWA) results were used for density estimation and genome-wide complex trait analysis (GCTA) to calculate the variance explained by all SNPs. Next, a fixed-effect inverse variance meta-analysis of the 3 GWA analyses was carried out. Finally, the overlap in results with prior GWA studies of childhood and adulthood psychiatric disorders and treatment responses was tested by examining whether SNPs associated with these traits jointly showed a significant signal for INT.

Results: Genome-wide SNPs explained 13% to 43% of the total variance. This indicates that the genetic architecture of INT mirrors the polygenic model underlying adult psychiatric traits. The meta-analysis did not yield a genome-wide significant signal but was suggestive for the PCSK2 gene located on chromosome 20p12.1. SNPs associated with other psychiatric disorders appeared to be enriched for signals with INT (λ = 1.26, p < .03).

Conclusion: Our study provides evidence that INT is influenced by many common genetic variants, each with a very small effect, and that, even as early as age 3, genetic variants influencing INT overlap with variants that play a role in childhood and adulthood psychiatric disorders.

Keywords: GCTA; GWA study; internalizing problems; pcsk2; variance explained.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

Child Behavior Disorders / genetics*
Child, Preschool
Cohort Studies
Female
Genome-Wide Association Study / statistics & numerical data*
Humans
Male
Polymorphism, Single Nucleotide / genetics*
Proprotein Convertase 2 / genetics*
Registries / statistics & numerical data*

Substances

PCSK2 protein, human
Proprotein Convertase 2